MX2007010025A - Pharmaceutical composition for treatment of ocular hypertension. - Google Patents
Pharmaceutical composition for treatment of ocular hypertension.Info
- Publication number
- MX2007010025A MX2007010025A MX2007010025A MX2007010025A MX2007010025A MX 2007010025 A MX2007010025 A MX 2007010025A MX 2007010025 A MX2007010025 A MX 2007010025A MX 2007010025 A MX2007010025 A MX 2007010025A MX 2007010025 A MX2007010025 A MX 2007010025A
- Authority
- MX
- Mexico
- Prior art keywords
- ocular hypertension
- treatment
- dorsolamide
- timolol
- brimonidine
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 26
- 206010030043 Ocular hypertension Diseases 0.000 title claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims abstract description 31
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960003679 brimonidine Drugs 0.000 claims abstract description 31
- 229960004605 timolol Drugs 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 230000003042 antagnostic effect Effects 0.000 claims abstract description 4
- 230000008901 benefit Effects 0.000 claims abstract description 3
- 230000002195 synergetic effect Effects 0.000 claims abstract description 3
- SNHBGEDHHQFRLN-XPUUQOCRSA-N CCN[C@H]1C[C@H](C)Sc2sc(cc12)S(N)(=O)=O Chemical compound CCN[C@H]1C[C@H](C)Sc2sc(cc12)S(N)(=O)=O SNHBGEDHHQFRLN-XPUUQOCRSA-N 0.000 claims description 37
- 229940079593 drug Drugs 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 21
- 230000009467 reduction Effects 0.000 claims description 10
- 230000003247 decreasing effect Effects 0.000 abstract description 4
- 229960003933 dorzolamide Drugs 0.000 abstract description 4
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 230000004410 intraocular pressure Effects 0.000 description 18
- 230000000694 effects Effects 0.000 description 14
- 239000002876 beta blocker Substances 0.000 description 13
- 230000000699 topical effect Effects 0.000 description 13
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 8
- 229940097320 beta blocking agent Drugs 0.000 description 8
- 208000010412 Glaucoma Diseases 0.000 description 7
- 230000000996 additive effect Effects 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 201000006366 primary open angle glaucoma Diseases 0.000 description 6
- 102000003846 Carbonic anhydrases Human genes 0.000 description 5
- 108090000209 Carbonic anhydrases Proteins 0.000 description 5
- 230000001077 hypotensive effect Effects 0.000 description 5
- 230000001603 reducing effect Effects 0.000 description 5
- IWEGDQUCWQFKHS-UHFFFAOYSA-N 1-(1,3-dioxolan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(CC2OCCO2)N=C1 IWEGDQUCWQFKHS-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 229940030611 beta-adrenergic blocking agent Drugs 0.000 description 4
- 229960001724 brimonidine tartrate Drugs 0.000 description 4
- 229940069275 cosopt Drugs 0.000 description 4
- OSRUSFPMRGDLAG-QMGYSKNISA-N dorzolamide hydrochloride Chemical compound [Cl-].CC[NH2+][C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 OSRUSFPMRGDLAG-QMGYSKNISA-N 0.000 description 4
- 238000002483 medication Methods 0.000 description 4
- 239000002997 ophthalmic solution Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 108010044467 Isoenzymes Proteins 0.000 description 3
- 238000011360 adjunctive therapy Methods 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 3
- 229960001160 latanoprost Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229940054534 ophthalmic solution Drugs 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 2
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 2
- 206010034960 Photophobia Diseases 0.000 description 2
- 241000593989 Scardinius erythrophthalmus Species 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000004509 aqueous humor production Effects 0.000 description 2
- 229960004424 carbon dioxide Drugs 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000004386 ocular blood flow Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000541 pulsatile effect Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000004304 visual acuity Effects 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- KSBKLOORIKSXDP-BWJWWNBBSA-N (2s)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol;(4r,6r)-4-(ethylamino)-6-methyl-7,7-dioxo-5,6-dihydro-4h-thieno[2,3-b]thiopyran-2-sulfonamide Chemical compound CCN[C@@H]1C[C@@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 KSBKLOORIKSXDP-BWJWWNBBSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 108010033547 Carbonic Anhydrase I Proteins 0.000 description 1
- 102100025518 Carbonic anhydrase 1 Human genes 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 206010043087 Tachyphylaxis Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 229960000722 brinzolamide Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000000546 chi-square test Methods 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229940024048 combination timolol Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940075885 dorzolamide / timolol Drugs 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000004493 normal intraocular pressure Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 229940126702 topical medication Drugs 0.000 description 1
- 229940100613 topical solution Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention is related to the pharmaceutical industry in general and in particular with the pharmaceutical industry of production of ophthalmic compositions. More specifically, the present invention relates to the pharmaceutical industry of production of ophthalmologic compositions for the treating of ocular hypertension. The advantage of the present invention against the present state of the technique is the fulfilling of a synergic effect of its components for the decreasing of ocular hypertension with no antagonistic effect between its components. The present invention consists of a pharmaceutical composition for the treatment of ocular hypertension characterized by comprising a pharmacologically effective amount of dorzolamide, with a pharmacologically effective amount of timolol and a pharmacologically effective amount of brimonidine.
Description
\
PHARMACEUTICAL COMPOSITION FOR EYE HYPERTENSION TREATMENT
FIELD OF THE INVENTION
The present invention relates to the pharmaceutical industry in general and to the pharmaceutical industry for the production of ophthalmic compositions in particular. More specifically, the present invention is related to the pharmaceutical industry for the production of ophthalmological drugs for ocular hypertension treatment.
BACKGROUND OF THE INVENTION
There are many therapeutic options when therapy with beta-blockers fails, to achieve the goal infra-ocular pressure. Two of the most frequent options are the fixed combination with dorsola-mide / timolol.
If the initial therapy is successful but additional IOP reduction is required, a topical drug such as an alpha2-adrenergic agonist, a topical carbonic anhydrase inhibitor or a prostaglandin analogue, is added to the beta-blocker.
according to the characteristics of the patient and the clinical condition of the patient. Subsequently, if the first combination of drugs has an additive effect but does not completely reach the clinical objectives, another drug can be added. This process can continue until there is a minimum increase in benefit and a maximum increase in cost and inconvenience for the patient. ((10) Marchetti A, Magar R, An P. Clinical and Economic Impact of new trends in glaucoma treatment Medscape General Medicine July, 2001)
Dorsolamide is an inhibitor of topical carbonic anhydrase that reduces intraocular pressure by decreasing the production of aqueous humor. It is frequently prescribed as adjunctive therapy to timolol to achieve additional infra-ocular pressure reduction. In controlled clinical studies, dorsolamide provides additional intraocular pressure reduction, this effect being clinically significant additive from 13 to 21% in the reduction of intraocular pressure when added to beta-blockers. ((11) Pfeiffer N. Dorzolamide: Developing and Clinical Application of a topical carbonic anhydrase inhibitor, Survey Ophhtalmology 1997; 42 (2): 137-151)
The additive effect of the decrease in intraocular pressure of two or more medications should be expected when these drugs are
used together with drugs that act by different mechanisms. The carbonic anhydrase inhibitors are additive to the beta-adrenergic blocking agents despite their mutual inhibition of aqueous humor production, because the mechanism of action of the beta-blocker does not reduce the activity of carbonic anhydrase. ((12) Brubaker R, Ingram C, Schoff E, et al., Comparison of the efficacy of betaxolol-brinzolamide and thyrole-dozolamide as supressors of aqueous humor flow in human sub-jects Ophthalmology 2000; 107: 283-287)
Brimonidine tartrate is a highly selective ocular agonist alpha-2 adrenergic receptor-lowering drug. Although brimonidine is structurally related to clonidine, brimonidine has greater selectivity for alpha-2-adrenergic receptors. Some studies suggest that brimonidine may be useful as adjunctive therapy to topical beta-blocker therapy, producing an additive effect reducing infraocular pressure of 5 and 3.7mmhg. ((13) A Useful New Topical treatment for glaucoma and ocular hypertension.Drug Ther Pers-pect 13 (1): 1 -4 1999)
2% dorsolamide and 0.2% brimonidine have well documented efficacy and tolerability profiles. When used as adjunctive therapy to treatment with topical beta-blockers in
adults with POAG or ocular hypertension, 0.2% brimonidine was found by Simmons to be effective in reducing IOP in more patients than dorsolamide by 2%. Alternatively, Cantor and colleagues found no statistically significant differences in efficacy of brimonidine and dorsolamide used adjunct in patients with POAG or ocular hypertension applying topical beta-blockers. ((14) Whitson J, henry C, Hughes B. Com-parison of the safety and efficacy of dorzolamide 2% and bri-monidine 0.2% in patients with glaucoma or ocular hypertension J Glaucoma 2004; 13: 168-173)
Ermis and colleagues evaluated the ocular hypotensive effect of dorsolamide at 2% in patients with intraocular pressure of at least 22 mm Hg treated with topical brimonidine, demonstrating the additional reducing effect of dorsolamide in these patients, decreasing up to 29% in a lapse 30 days
Brimonidine and dorsolamide, used individually as mono-therapy, have a similar ocular hypotensive effect. It has been reported that dorsolamide reduces IOP 20% when it is added to you moiol, indicating good additive effect of dorsolamide and ti m or I or l. Brimonidine decreases IOP by reducing the production of aqueous humor and increasing the flow of the eoscleral pathway. Brimonidine and dorsolamide can be an effective combination. ((fifteen)
Ermis S, Ozturk F, Ubeyt Umit. The short term PlO-lowering effect of brimonidine 0.2% and dorzolamide 0.2% combination in primary open-angle glaucoma. Acta Ophthalmol Scand. 2002: 80: 632-634) The success of glaucoma treatment is based not only on efficacy but also on adverse effects and patient compliance with treatment. The prevalence of noncompliance, or failure to take medications as prescribed, is high in glaucoma patients in a range of 27% to 56%, depending on the population and the measurement method. With the availability of new ophthalmic products, maximum medical therapy can become increasingly complex because the new products have different duration of action and different prescription schemes. Its use in conjunction with other topical agents can take 30 to 60 minutes twice a day for an appropriate application. These types of treatments can have serious economic implications for patients. The more complicated the treatment, the less compliance there is. ((10 Marchetti op cit.)
In addition to this, numerous studies have shown that the chronic use of hypotensive drugs can cause significant changes on the ocular surface since the prolonged use of topical medications containing preservatives can induce changes in the ocular surface and damage the conjunctival epithelial cells and corneal as well as abnormal cell infiltration
inflammatory and / or fibroblastic markers. ((16) Noecker R, Herygers L, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications Corna 2004; 23: 490-496; 17) Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface in-flammatory changes induced by topical antiglaucoma drugs. Ophthalmology.1999; 106: 556-563)
Historically, additional agents were typically administered with beta-blockers in a concomitant manner. However, a current trend in the development of drugs in glaucoma has been the fixed combination of two agents.
Januleviciene and cois. (Januleviciene I, Harris A, Kagemann L, et al.) A comparison of the effects of dorzolamide / timolol fixed combination versus latanoprost on infraocular pressure and pulsatile ocular blood flow in primary open-angle glaucoma patients Acta Ophthal-mol Scand. 2004; 82: 730-737) conducted a study to assess the effects of the fixed combination dorsolamide / timolol, comparing it with latanoprost on intraocular pressure in 30 patients with primary open-angle glaucoma (20). The fixed combination dorsolamide / timolol and latanoprost showed a statistically significant reduction in intraocular pressure, 4.6mmHg and 3.75mmHg respectively, and had an increase in pulsatile ocular blood flow of 2.048 Ml / second and
2. 147 1 / second respectively.
Timolol is a nonselective beta-adrenergic blocking agent of B1 and B2 receptors, which reduces elevated intraocular pressure, as well as normal intraocular pressure. The onset of the action with a drop of can be detected within the first hour after its ocular topical instillation, with a maximum effect observed at 2 to 4 hours. A significant reduction in intraocular pressure can be maintained for periods up to 24 hours with a single dose. The drug can be absorbed systemically and cause a decrease in heart rate, cardiac arrhythmias and bronchial spasm. Timolol exerts little or no effect on pupil size or accommodation. (1,7)
It has not been possible to elucidate the degree of systemic absorption that occurs after the topical application of timolol. After ocular topical administration of a 0.5% timolol drop, the onset of action can be detected within the first hour after ocular topical instillation. The maximum effect of timolol occurs at 2 hours and this effect lasts more than 24 hours. The efficacy of these drugs may decrease somewhat over time (tachyphylaxis), although the ocular hypotensive effect has been maintained successfully for up to three years. The beta-adrenergic antagonists do not reduce intraocular pressure during sleep.
When administered topically, dorsolamide rapidly reaches the systemic circulation and quickly binds to erythrocytes. Human erythrocytes contain the carbonic anhydrase isoenzymes I and II. Liquid chromatography has identified a metabolite of dorsolamide, desmethylated n-dorsolamide. The dorso-lamida has greater affinity for the isoenzyme II of carbonic anhydrase, while the N-desetilated metabolite has a greater affinity for carbonic anhydrase I. The dorsolamide binds moderately to the plasma proteins (approximately 33%). After 4 weeks of bilateral treatment, the activity of the carbonic anhydrase isoenzyme decreases 21% of the basal activity.
Fluorophotometric studies in animals and humans suggest that brimonidine tartrate solution reduces intraocular pressure by decreasing aqueous humor production and increasing uveoscleral flow. Peak ocular hypotensive effects occur 2-3 hours after topical administration of brimonidine tartrate ophthalmic solution.
The use of combinatorial therapies presents serious deficiencies when one application is used after the other. For the treatment of some ophthalmological pathologies, combinations of carbonic anhydride inhibitors and beta-adrenergic blocking agents have been proposed.
It has not been conclusively demonstrated that all carbonic anhydride inhibitors and all beta-adrenergic blocking agents are efficient for the treatment of ocular hypertension. On the other hand, it has not been demonstrated whether in the combinations there is an antagonistic effect in the action of the combination of these types of agents.
Nor has it been studied whether there is a reaction between these components when formulating the composition.
OBJECTIVES OF THE INVENTION
One of the objects of the invention is to achieve a composition with synergistic effect of its components for the reduction of ocular hypertension.
Another objective is to determine the quantitative composition of these drugs.
Still another objective is to determine if in the combinations that achieve the first objective there are chemical reactions that produce modification in the active molecules.
Still another objective of the present invention is to demonstrate that there is no antagonistic effect between the components.
And all those objectives that will become apparent with the present description and the annexes included.
BRIEFING THE INVENTION
In brief the present invention consists of a novel qualitative composition for the treatment of ocular hypertension consisting of the combination of dorsolamide, timolol and brimo-nidine.
In one of its embodiments, the present invention consists of a quantitative composition of 0.5% timolol, 2% dorsolamide and 0.2% brimonidine.
The selection of these components was carried out by means of the de-termination of which products are more efficient and effective in their sequential use.
Dorsolamide, timolol and brimonidine have been formulated as a combined product that will provide a more convenient regimen for
patients who require multiple medications. The reduction in the number of products and the number of facilities required daily can improve the degree of compliance and reduce the dilution effect of two different drops applied immediately to each other and consequently improve the control of intraocular pressure, as well as decrease the risk associated with the chronic use of multi-dose ophthalmic solutions with conservative.
Subsequent to this determination, the in vivo efficiency of these combinations was evaluated to determine the non-competition between them in their effect on ocular pressure.
Likewise, the non-reaction of the molecules with each other was determined by being in combination.
As a collateral determination, the evolution of the red eye severity index and the burn improvement index were evaluated to evaluate said composition.
For a better understanding of the invention, the detailed description of the present invention will be made showing the results of the various tests carried out with the selected composition.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the graph of the evolution of the ocular pressure in the axis of the ordinates and the time in the axis of the abscissa for the treatments with the combination timolol to 0.5%, dorso-lamida to 2% and brimonidine to 0.2% .
Figure 2 is the graph showing the evolution of the red eye severity index on the ordinate axis and the time on the abscissa axis.
Figure 3 shows the index of improvement of the ardor in the axis of the ordinates and the time in the axis of the abscissa
Figure 4 shows the chromatogram where the peaks of brimonidine and dorsolamide of an initial standard were printed.
Figure 5 is from the dorsolamide and brimonidine chromatogram of a freshly prepared batch of dorsolamide, brimonidine and timolol.
Figure 6 is the chromatogram of a run of the standards at the time of running the same batch that served to determine the chromatogram of Figure 5, six months later.
Figure 7 is the chromatogram of the same batch that resulted in the graph with the peaks of Figure 5, but six months later.
Figure 8 shows the chromatogram with the peak of timolol in a standard at the time of the initial assessment of timolol in the batch of the previous chromatograms.
Figure 9 shows the chromatogram with the peak of timolol in a freshly prepared lot of dorsolamide, brimonidine and timolol, which is the same batch of the different chromatogram where lot is mentioned.
Figure 10 is the chromatogram of the same batch that was run for the chromatogram of Figure 9, but 6 months later.
For a better understanding of the invention, the detailed description of the invention will be made showing the best way to carry out the invention and complying with the enabling characteristic to a third party with average knowledge in the field.
DETAILED DESCRIPTION OF THE INVENTION
Comparative multicentre study of the safety and efficacy of a sterile ophthalmic solution based on 0.5 thymolol, 2% dorsolamide, 0.2% brimonidine tartrate.
The purpose of the study was to evaluate the safety, tolerance and efficacy of an ophthalmic solution of 0.5% timolol, 2% dorsolamide and 0.2% brimonidine in fixed combination (Krytantek Of-teño®) elaborated by Laboratorios Sophia SA. of C.V. and compare them with those of a topical solution of dorsolamide and timolol (Co-sopt®) in patients diagnosed with Primary Open-Angle Glaucoma and / or ocular hypertension with or without pseudoexfoliation.
MATERIAL AND METHODS
A multicentre, prospective, randomized and double-blind study was carried out, in which patients with a diagnosis of Primary Open Angle Glaucoma and / or ocular hypertension were selected, divided into two treatment groups, which were evaluated during a period of 3 months. During this time, one of the groups received randomly and blinded, one drop every 12 hours of Krytantek Ofteno® (0.5% timolol, 2% dorsolamide and
0.2% brimonidine, Sophia Laboratories) while the other group was treated under equal conditions with Cosopt® (0.5% timolol and 2% dorsolamide, MSD Laboratories). The efficacy and safety parameters evaluated included visual acuity (Log-Mar), intraocular pressure (IOP) with Goldman tonometer, evaluation of visual fields with Humphrey automated perimetry (strategy 24-2 white / white), Bengal Rose stains and fluorescein, conjunctival hyperemia, evaluation of the corneal surface, pain, photophobia and foreign body sensation. The results of the study were subjected to a statistical inference analysis! using the Student's T tests for independent samples, Wilcoxon, Mann-Whitney U and the Chi-square test.
RESULTS
With the participation of 12 different research centers, a total of 104 patients were included (25.5% men and 74.5% women), with an average age of 58 years. Through the Mann-Whitney test, both drugs showed a significant reduction in IOP, marking significant differences when compared with their own basal average values (intragru-po), while the behavior of these values comparing the group that received Krytantek Ofteno® showed statistical differences
Significantly (p <0.05) with respect to Cosopt® (Figure 1), in favor of Krytantek Ofteno®.
Regarding visual acuity, Benga-la and f luorescein a stain, evolution of visual fields, corneal surface state, photophobia and foreign body sensation, no statistically significant differences were found between both groups. length of the treatment. However, in terms of burning and conjunctival hyperemia, the Krytantek Ofteno treatment group showed lower values when compared with Cosopt (Chi-Square p <0.05), at day 90 of treatment (Figures 2 and 3).
CONCLUSIONS:
According to the results obtained, we can conclude that Krytantek Ofteno® is more effective than Cosopt® in reducing the Infraocular Pressure in patients with Primary Open-Angle Glaucoma and / or Ocular Hypertension, also showing a statistically significant tendency of greater tolerance in patient users for Krytantek Ofteno®.
With respect to the stability of the different components of the composition object of the present description, differences were made
run on a chromatograph to measure the different changes in the molecules.
For the runs always requires a standard to verify the coincidence of the peaks. Figure 4 shows the chromatogram where the peaks of brimonidine and dorsolamide of an initial standard were printed. This was a secondary standard of a USP standard.
Figure 5 is from the dorsolamide and brimonidine chromatogram of a freshly prepared batch of dorsolamide, brimonidine and timolol. This is the lot to which 6 months later the same determination was made.
Figure 6 is the chromatogram of a run of the standards at the time of running the same batch that served to determine the chromatogram of Figure 5, six months later. This standard was prepared at the time of making the runs to minimize the error.
Figure 7 is the chromatogram of the same batch that resulted in the graph with the peaks of Figure 5, but six months later. The batch was preserved under extreme conditions to correctly evaluate the stability of the different molecules.
Figure 8 shows the chromatogram with the peak of timolol in a standard at the time of the initial assessment of timolol in the lot of the previous chromatograms
Figure 9 shows the chromatogram with the peak of timolol in a freshly prepared lot of dorsolamide, brimonidine and timolol, which is the same batch of the different chromatogram where lot is mentioned. The separation of this chromatogram from the rest was carried out for a better clarity of the diagram.
Figure 10 is the chromatogram of the same batch that was run for the chromatogram of Figure 9, but 6 months later.
The invention has been sufficiently described so that a person with average skill in the art can reproduce and obtain the results that we mentioned in the present invention. However, any person skilled in the art who is competent in the present invention may be able to make modifications not described in the present application, however, if for the application of these modifications in a certain determined composition, the As claimed in the following claims, said processes and solutions should be understood within the scope of the invention.
Claims (5)
1. Pharmaceutical composition for treating ocular hypertension characterized by comprising a pharmacologically effective amount of dorsolamide, with a pharmacologically effective amount of timolol and a pharmacologically effective amount of brimonidine.
2. Pharmaceutical composition for treatment of ocular hypertension, as claimed in the preceding claim, characterized in that the percentage of dorsolamide is 2% w / w with respect to the final composition.
3. Pharmaceutical composition for treatment of ocular hypertension, as claimed in claim 1 or 2, characterized in that the percentage of timolol is 0.5% weight / weight with respect to the final composition.
4. Pharmaceutical composition for treatment of ocular hypertension, as claimed in any of claims 1 to 3, characterized in that the percentage of brimonidine is 0.2% weight / weight with respect to the final composition.
5. Pharmaceutical composition for treatment of ocular hypertension, as claimed in claim 1, characterized in that the percentage of dorsolamide is 2.0% w / w with respect to the final composition; the percentage of timolol is 0.5% weight / weight with respect to the final composition and the percentage of brimonidine is 0.2% weight / weight with respect to the final composition. SUMMARY The present invention relates to the pharmaceutical industry in general and to the pharmaceutical industry for the production of ophthalmic compositions in particular. More specifically, the present invention is related to the pharmaceutical industry for the production of ophthalmological drugs for ocular hypertension treatment. The advantage of the present invention over those of the state of the art is to achieve a synergistic effect of its components for the reduction of ocular hypertension without antagonistic effect between the components. The present invention consists of a pharmaceutical composition for treatment of ocular hypertension characterized by comprising a pharmacologically effective amount of dorsolamide, with an effective pharmaco-logically effective amount of timolol and a pharmacologically effective amount of brimonidine.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX2007010025A MX2007010025A (en) | 2007-08-17 | 2007-08-17 | Pharmaceutical composition for treatment of ocular hypertension. |
| EP08380005A EP2033649A1 (en) | 2007-08-17 | 2008-01-10 | Pharmaceutical composition for treatment of ocular hypertension |
| US12/013,403 US20090048261A1 (en) | 2007-08-17 | 2008-01-11 | Pharmaceutical Composition for Treatment of Ocular Hypertension |
| JP2008004108A JP2009102290A (en) | 2007-08-17 | 2008-01-11 | Pharmaceutical composition for treating ocular hypertension |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX2007010025A MX2007010025A (en) | 2007-08-17 | 2007-08-17 | Pharmaceutical composition for treatment of ocular hypertension. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2007010025A true MX2007010025A (en) | 2009-02-25 |
Family
ID=40251771
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2007010025A MX2007010025A (en) | 2007-08-17 | 2007-08-17 | Pharmaceutical composition for treatment of ocular hypertension. |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20090048261A1 (en) |
| EP (1) | EP2033649A1 (en) |
| JP (1) | JP2009102290A (en) |
| MX (1) | MX2007010025A (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2012113380A (en) | 2009-09-07 | 2013-10-20 | Микро Лабс Лимитед | OPHTHALMIC COMPOSITIONS CONTAINING DORZOLAMIDE, THYMOL AND BRIMONIDINE |
| US9522153B2 (en) | 2009-12-22 | 2016-12-20 | Allergan, Inc. | Compositions and methods for lowering intraocular pressure |
| ES2709180T3 (en) | 2010-07-29 | 2019-04-15 | Allergan Inc | Brimonidine and timolol solutions without preservatives |
| KR101119610B1 (en) * | 2010-12-02 | 2012-03-06 | 한림제약(주) | Opthalmic liquid composition comprising dorzolamide, timolol, and brimonidine |
| KR20130006744A (en) | 2011-04-05 | 2013-01-18 | 삼성전자주식회사 | Method of manufacturing a mask and apparatus for performing the same |
| US20190038598A1 (en) * | 2016-02-22 | 2019-02-07 | Santen Pharmaceutical Co., Ltd. | Pharmaceutical composition including dorzolamide and brimonidine |
| KR20190097104A (en) * | 2016-12-15 | 2019-08-20 | 해로우 헬스 인코포레이티드 | Pharmaceutical formulations for the treatment of glaucoma and methods of making and using the same |
| US20180318319A1 (en) | 2017-05-04 | 2018-11-08 | Ocular Science, Inc. | Compositions and Methods for Treating Eyes and Methods of Preparation |
| EP3843721A4 (en) * | 2018-08-29 | 2022-10-12 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
| US11071724B2 (en) | 2019-05-17 | 2021-07-27 | Ocular Science, Inc. | Compositions and methods for treating presbyopia |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7030149B2 (en) * | 2002-04-19 | 2006-04-18 | Allergan, Inc. | Combination of brimonidine timolol for topical ophthalmic use |
| WO2006082588A2 (en) * | 2005-02-07 | 2006-08-10 | Pharmalight Inc. | Method and device for ophthalmic administration of active pharmaceutical ingredients |
| MX2009000885A (en) * | 2006-07-25 | 2009-02-05 | Osmotica Corp | Ophthalmic solutions. |
-
2007
- 2007-08-17 MX MX2007010025A patent/MX2007010025A/en not_active Application Discontinuation
-
2008
- 2008-01-10 EP EP08380005A patent/EP2033649A1/en not_active Withdrawn
- 2008-01-11 JP JP2008004108A patent/JP2009102290A/en active Pending
- 2008-01-11 US US12/013,403 patent/US20090048261A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP2033649A1 (en) | 2009-03-11 |
| JP2009102290A (en) | 2009-05-14 |
| US20090048261A1 (en) | 2009-02-19 |
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